Adane L, Bharatam P V
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar-160 062, India.
Indian J Pharm Sci. 2010 May;72(3):324-33. doi: 10.4103/0250-474X.70478.
A molecular docking study was carried out on 28 compounds belonging to 2,4-diaminoquinazoline and 2,4-diaminopteridine analogs using Glide, FlexX and GOLD programs and the X-ray crystallographic structures of the quadruple mutant (1J3K:pdb) and wild type (1J3I:pdb) Plasmodium falciparum dihydrofolate reductase enzyme. The experimental conformation the bound ligand WR99210 was precisely reproduced by the docking procedures as demonstrated by low (<2.00 Å) root-mean-square deviations. The results indicated that most of the compounds dock into the active sites of both the wild type and quadruple mutant P. falciparum dihydrofolate reductase enzymes. Visual inspection of the binding modes also demonstrated that most of the compounds could form H-bond interactions with the key amino acid residues (Asp54, Ile14 and Leu/Ile164) and with better docking scores than the bound compound (5). Their long side chains orient in the hydrophobic portion of the active site which is occupied by trichloro aryloxy side chain of WR99210 (5). Thus, avoid potential steric clashes with Asn108 (mutated from Ser108). Such a clash is known to be responsible for the resistance of the P. falciparum to pyrimethamine and cycloguanil.
使用Glide、FlexX和GOLD程序以及恶性疟原虫二氢叶酸还原酶四重突变体（1J3K:pdb）和野生型（1J3I:pdb）的X射线晶体结构，对属于2,4-二氨基喹唑啉和2,4-二氨基蝶啶类似物的28种化合物进行了分子对接研究。对接程序精确再现了结合配体WR99210的实验构象，低均方根偏差（<2.00 Å）证明了这一点。结果表明，大多数化合物对接至野生型和四重突变型恶性疟原虫二氢叶酸还原酶的活性位点。结合模式的可视化检查还表明，大多数化合物能够与关键氨基酸残基（Asp54、Ile14和Leu/Ile164）形成氢键相互作用，并且对接分数优于结合化合物（5）。它们的长侧链朝向活性位点的疏水部分，该部分被WR99210的三氯芳氧基侧链占据（5）。因此，避免了与Asn108（由Ser108突变而来）的潜在空间冲突。已知这种冲突是恶性疟原虫对乙胺嘧啶和环氯胍产生抗性的原因。
